3.2.4　Extracellular Matrix (ECM)

The ECM, a complex assembly of collagen, proteoglycans and other molecules, is an important constituent of normal tissues and provides essential cues for cell development, migration, adhesion,proliferation, survival, and other metabolic functions.The principal proteins in ECM are fibrous proteins (collagen, elastin, fibronectin, laminin) and proteoglycans (chondroitin sulphate, heparin sulphate, keratin sulphate and hyaluronic acid) contributing to tissue stiffness and to constitution of basement membrane, which functions as a barrier among tumor cells and stroma.When we refer to ECM, we not only consider the protein as a principal component but also include cytokines, growth factor, hormones secreted by stromal and tumor cells, physical and chemical parameters such as pH,oxygen tension, interstitial pressure, and fluid flux regulating cancer progression and metastatic dissemination.In animal models and in clinical studies, intra-tumoral hypoxia, loss-of-function for VHL gene, gain-of-function for oncogenes, viral transforming genes, and increase in hypoxia-inducible factors (HIFs) activity correlated with tumor growth, vascularization, and metastasis.HIF-1 activates transcription of genes encoding proteases that degrade (CTSC, MMP2,MMP9, MMP14, PLAUR) or remodel (LOX, LOXL2, LOXL4) the extracellular matrix within the primary tissue and at distant sites of metastasis.Additionally, it activates motility factors (AMF,MET), permeability factors (VEGF, ANGPT2) promoting the intravasation of cancer cells into blood vessels, cell surface (L1CAM), and secreted (ANGPTL4) proteins responsible for extravasation of cancer cells into the parenchyma at metastatic sites.HIFs also regulate cell proliferation and survival by binding hypoxia responsive element in the genes encoding for VEGF,stromal cell-derived factor 1 (SDF-1 also known as CXCL12), TGF-α, angiopoietin, PDGFβ,placental growth factor (PGF), FGF2, and connective tissue growth factor (CTGF).Integrins are cell surface receptors regulating interactions between the cell and the ECM proteins in order to mediate adhesion to the extracellular matrix.After this interaction, these proteins activate several molecular signaling such as focal adhesion kinases (FAKs), Src family kinases (SFKs), and scaffolding molecules, such as p130 CRK-associated substrate (p130CAS; also known as BCAR1)contributing to focal cellular adhesion.In addition, they recruit proteins such as talin, paxillin,α-actinin, tensin and vinculin coupling the ECM to the actin cytoskeleton.An increasing interest is focused on the relationship between integrin and cancer because several studies reported that integrins are significantly up-regulated in a number of solid tumors involved in tumorigenesis and tumor progression [32,45].(https://www.daowen.com)

Volociximab, IgG4 monoclonal antibody (mAb) against α5β1 integrin, was evaluated in phase I study in solid tumors.Although its antitumor activity was not confirmed, the good safety profile encouraged testing this drug in combination with chemotherapy in non-small cell lung cancer.This combination showed some efficacy considering that 24% of patients achieved a partial response and 52% stable disease with a safe toxicity profile [46].